Heart failure does not only affect the heart; it also involves skeletal muscle and the endocrine and immune systems.1 Heart failure is characterized by increased levels of cortisol and immune activation, combined with decreased levels of the anabolic hormones testosterone and IGF-1.1-4 Data also suggest that patients with heart failure have both insulin resistance and growth hormone resistance.3 This metabolic shift favors catabolism and reduction in muscle mass, muscle function and exercise capacity, which are common manifestations in heart failure patients.5-9 Importantly, low levels of free testosterone in men with heart failure are independently associated with increased mortality.10

Here we summarize the results of a study published in Mayo Clinic Proceedings, which investigated the effects of testosterone treatment combined with exercise training in patients with heart failure who have testosterone deficiency.11

Key Points

Testosterone deficiency is common among men with heart failure, affecting up to 60%.

The main symptom of heart failure is exercise intolerance, which is due not to a “failing heart” but due to premature fatigue and muscle atrophy.

Testosterone treatment combined with exercise in heart failure patients is superior for increasing maximal power output and skeletal muscle size, as well as for reducing muscle sympathetic nerve activity.

What is known about testosterone and heart failure

Testosterone deficiency is common among men with heart failure.1-4 Low testosterone levels are seen in all NYHA classes of heart failure, compared to age-matched healthy male controls.4 Notably, while a decline in testosterone levels is common among men as they get older, this phenomenon is much faster in men with heart failure (regardless of class of heart failure) than in healthy men, and it is more evident in younger men below 45 years of age.4 This reduction in testosterone levels is independently related to exercise intolerance; the greater the reduction in testosterone levels, the more severe the progression of exercise intolerance.9 Low testosterone is also an independent risk factor for hospital readmission and increased mortality in men with heart failure.4,10,12

Four previous studies have investigated the effect of testosterone treatment in hypogonadal men with heart failure. The first study demonstrated that treatment with testosterone for 3 months significantly improved walking distance, but there were no effects on muscle strength or body weight.13 Another study showed that 12 months of testosterone treatment significantly improved exercise capacity by 15% in heart failure patients treated with testosterone compared to those treated with placebo.14 There was also an improvement in symptoms by at least one functional class in the testosterone group.14 This study concluded that testosterone treatment improves functional capacity and symptoms in men with moderately severe heart failure.14 In another study, the same research team found that testosterone treatment, compared to placebo, improved insulin sensitivity and body composition (reduced body fat mass and increased body weight).15

In the fourth study, heart failure patients were randomly allocated to receive, on top of optimal medical therapy, either intramuscular long-acting testosterone undecanoate (1,000 mg Nebido) or placebo (saline) injections at baseline and at 6 and 12 weeks.16 Both groups had similar baseline total and free testosterone levels in the 210 – 230 ng/dL and 11.3 – 12.1 pg/dL range, respectively. Testosterone treatment increased total testosterone to 520 ng/dL and free testosterone to 32 pg/mL. No changes in testosterone levels were seen in the placebo group. Results showed that testosterone treatment improved insulin sensitivity, aerobic capacity (VO2), minute ventilation (VE/VCO2 slope), forearm and leg strength, and baroreflex sensitivity.16 The increase in functional capacity and muscular strength was related to the increase in plasma levels of testosterone and not related to changes in left ventricular function.16

An increased muscle sympathetic nerve activity is seen in patients with low testosterone.12 Increased muscle sympathetic nerve activity - and by association, low testosterone 12 - are hallmarks of heart failure and are independent markers of mortality.10,17 In experimental models of heart failure it has been demonstrated that sympathetic hyperactivity is a major factor contributing to skeletal muscle wasting.18

Exercise training in patients with heart failure is safe and reduces all-cause mortality and cardiovascular mortality, as well as hospitalizations.19-21 A moderate supervised aerobic exercise training performed twice weekly for 10 years was found to maintain functional capacity and confer a sustained improvement in quality of life compared with non-training patients.22 These sustained improvements were associated with a reduction in major cardiovascular events, including hospitalizations for heart failure and cardiac mortality.22 Exercise training in the form of three 60 min exercise sessions per week, at heart rate levels that corresponded up to 10% below the respiratory compensation point, for 4 months, also reduces resting sympathetic nerve activity heart failure patients.23

However, little is known about the combined effects of testosterone treatment and exercise training in patients with heart failure with testosterone deficiency.

What this study adds

The present study was undertaken to investigate whether combined testosterone treatment and exercise training would potentiate the beneficial effects of each treatment in isolation. Out of 162 male patients with heart failure, 92 (57%) were found to have testosterone deficiency, confirming its high prevalence in this patient population.

Muscle sympathetic nerve activity was measured with microneurography, forearm blood flow with plethysmography, body composition with dual X-ray absorptiometry, and functional capacity with cardiopulmonary test. Skeletal muscle biopsy was performed in the vastus lateralis. Quality of life was assessed with the Minnesota Living with Heart Failure Questionnaire.

Results showed that muscle sympathetic nerve activity significantly decreased in the exercise and testosterone + exercise groups, whereas no changes were observed in the testosterone only group. Forearm blood flow was similar in all groups. Maximal power output increased most in the testosterone + exercise group, and this increase was significantly greater compared to the exercise only group (figure 1). There was a marked improvement in quality of life in the testosterone + exercise and the exercise groups. The greatest quality of life improvement was seen in the testosterone + exercise group (figure 2).

Figure 1: Change in Functional Capacity in Men with Heart Failure After 4 months of Exercise, Testosterone Undecanoate and Exercise combined with Testosterone Undecanoate.

Lean mass significantly increased in the exercise and testosterone + exercise groups, whereas lean mass decreased in the testosterone only group. The cross-sectional area of type I and type II fibers increased in the training + testosterone group when compared to testosterone only group.

It was concluded that testosterone treatment combined with exercise training provides a superior effect on muscle sympathetic nerve activity, muscle wasting, and functional capacity in patients with heart failure who are testosterone deficient.

Commentary

This is the first study to show a superior effect of testosterone treatment combined with exercise in heart failure patients for reducing muscle sympathetic nerve activity and preventing muscle atrophy, both of which are markers of poor outcome. This combination treatment was found to not only prevent muscle atrophy but actually result in a gain in lean mass, which was due to increased size of both type I (slow twitch) and type II (fast twitch) muscle fibers.

The main symptom of heart failure in an intolerance physical effort due to premature fatigability and dyspnea.24 However, these symptoms do not result directly from the impairment of function of the heart as a pump. Instead, the exercise intolerance in heart failure is due to disorders within tissues and organs outside the circulatory system.25-28 According to the “muscle hypothesis”, in heart failure patients, an exaggerated ergoreflex activation occurs in exercising muscles, which leads - via activation of sympathetic system - to fatigue and an excessive ventilatory response in a form of dyspnea.25,27,28 The muscle hypothesis states that structural and functional changes in skeletal muscles (i.e. skeletal myopathy) – alongside neurohormonal activation - are the main reason for impaired exercise capacity in patients with chronic heart failure.26,27,29,30 The study presented here provides evidence that testosterone treatment combined with aerobic exercise increases exercise intolerance by improving the mechanisms outlined in the muscle hypothesis.

The study authors stated that testosterone treatment alone did not seem to be useful in these patients in the absence of exercise, because it was not sufficient to avoid muscle wasting. However, stating that “testosterone treatment alone did not seem to be useful in these patients” counters results from the four previous studies mentioned above. 13-16 Another more recent study showed that unlike heart failure patients receiving placebo, those who received testosterone treatment alone had a significant improvement in functional capacity (6 min walk distance) and quality of life.31

The lack of effect on muscle wasting in the present study may be due to methodological issues. The patients in the testosterone alone treatment group were more frail (their baseline body weight was 7 kg less than that in the testosterone treatment plus exercise group). In addition, 4 months of testosterone treatment alone is a too short time span to see significant effects on muscle gains.32 There was also a significant increase in body fat in the testosterone treatment plus exercise group, while body fat in the testosterone only group tended to decrease. Therefore, a longer term study with patients that are better matched for baseline body weight and body composition parameters is warranted.

Only one previous study has investigated the effect of testosterone treatment combined with exercise.33 The testosterone treatment plus exercise group showed significant improvements in peak oxygen uptake, Beck Depression Inventory, leg strength, and several Medical Outcomes Study Short-Form quality of life domains, which were generally not apparent in the exercise plus placebo group.33 Thus, testosterone treatment combined with exercise training is safe, feasible and positively impacts a wide range of key health outcomes in elderly male patients with chronic heart failure who have a low testosterone levels.11,33